Myocardial infarction leads to millions of deaths per year. Clinical strategies to address this heart muscle destruction are essentially palliative or ineffective. For phase 2 (years 6-10) of this Bioengineering Research Partnership, we take knowledge gained in years 1-5 and apply this to developing an engineering system for clinical repair of damaged heart muscle. Specifically, we use proliferating human cardiomyocytes and a novel pro-angiogenic porous scaffold (both developed in years 1-5 of this program) to engineer 300?m diameter rods of cardiac muscle (RCM) or particles of cardiac muscle (PCM) that can be injected into a heart infarct zone and facilitate functional repair of cardiac muscle. The in vitro tissue engineering of cardiac muscle by itself, though an important step, is insufficient - this new muscle must survive, grow, integrate into the heart and, ultimately, enhance systolic function. Our engineering systems approach will evolve an integrated therapeutic strategy addressing these issues. We envision that, as early as possible after a myocardial infarction, a series of minimally invasive interventions will be implemented to reduce fibrosis, promote angiogenesis and limit further heart damage. RCM or PCM then will be implanted in this "primed" infarct. Ischemic death of these myocardial constructs will be minimized via the geometry of the implant, strategies to "harden" cardiomyocytes to ischemic injury, and novel approaches to induce rapid angiogenesis. Electrical integration of the implant is essential, and therefore we will optimize the electrophysiologic properties of the construct. The partnership's efforts to develop this heart muscle repair system are centered around four broad aims: (1) the tissue engineering of heart muscle rods and particles using rationally designed porous scaffolds and proliferating cardiomyocytes derived from human embryonic stem cells (approved lines GEO01.07;WA01, 07, 14), (2) priming the infarct site to prepare the tissue bed to accept the implant by controlling extracellular matrix components and inducing blood vessel formation, (3) developing surgical approaches to deliver the tissue-engineered rods or particles into the infarct and molecular approaches to promote implant survival, and (4) assessing structural and functional benefit to the infarcted heart. This comprehensive approach to heart muscle repair will be implemented by a collaborative, multidisciplinary team closely integrating engineers, scientists and clinicians.